Sulfonamides

ABSTRACT

The present invention provides R, R 1 , R 2 , R 3 , X, c, d, e, f, g, x, y, a, b, z and n are defined in the specification. These compounds are useful in lowering IOP and/or treating glaucoma or providing neuroprotection to the eye of a human patient.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is based on, and claims the benefit of, U.S.Provisional Application No. 60/710,537, filed Aug. 22, 2005, and whichis incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel sulfonamides which are useful inlowering intraocular pressure and/or glaucoma. These compounds alsoprovide neuroprotection to the eye of a human.

2. Description of the Related Art

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupillary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical α-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

It has long been know that one of the sequelae of glaucoma is damage tothe optic nerve head. This damage, referred to as “cupping”, results indepressions in areas of the nerve fiber of the optic disk. Loss of sightfrom this cupping is progressive and can lead to blindness if thecondition is not treated effectively.

Unfortunately lowering intraocular pressure by administration of drugsor by surgery to facilitate outflow of the aqueous humor is not alwayseffective in obviating damage to the nerves in glaucomatous conditions.This apparent contradiction is addressed by Cioffi and Van Buskirk[Surv. of Ophthalmol., 38, Suppl. p. S107-16, discussion S116-17, May1994] in the article, “Microvasculature of the Anterior Optic Nerve”.The abstract states:

-   -   The traditional definition of glaucoma as a disorder of        increased intraocular pressure (IOP) oversimplifies the clinical        situation. Some glaucoma patients never have higher than normal        IOP and others continue to develop optic nerve damage despite        maximal lowering of IOP. Another possible factor in the etiology        of glaucoma may be regulation of the regional microvasculature        of the anterior optic nerve. One reason to believe that        microvascular factors are important is that many microvascular        diseases are associated with glaucomatous optic neuropathy.

Subsequent to Cioffi, et al., Matusi published a paper on the“Ophthalmologic aspects of Systemic Vasculitis” [Nippon Rinsho, 52 (8),p. 2158-63, August 1994] and added further support to the assertion thatmany microvascular diseases are associated with glaucomatous opticneuropathy. The summary states:

-   -   Ocular findings of systemic vasculitis, such as polyarteritis        nodosa, giant cell angitis and aortitis syndrome were reviewed.        Systemic lupus erythematosus is not categorized as systemic        vasculitis, however its ocular findings are microangiopathic.        Therefore, review of its ocular findings was included in this        paper. The most common fundus finding in these diseases is        ischemic optic neuropathy or retinal vascular occlusions.        Therefore several points in diagnosis or pathogenesis of optic        neuropathy and retinal and choroidal vaso-occlusion were        discussed. Choroidal ischemia has come to be able to be        diagnosed clinically, since fluorescein angiography was applied        in these lesions. When choroidal arteries are occluded,        overlying retinal pigment epithelium is damaged. This causes        disruption of barrier function of the epithelium and allows        fluid from choroidal vasculatures to pass into subsensory        retinal spaces. This is a pathogenesis of serous detachment of        the retina. The retinal arterial occlusion formed non-perfused        retina. Such hypoxic retina released angiogenesis factors which        stimulate retinal and iris neovascularizations and iris        neovascularizations may cause neovascular glaucoma.

B. Schwartz, in “Circulatory Defects of the Optic Disk and Retina inOcular Hypertension and High Pressure Open-Angle Glaucoma” [Surv.Ophthalmol., 38, Suppl. pp. S23-24, May 1994] discusses the measurementof progressive defects in the optic nerve and retina associated with theprogression of glaucoma. He states:

-   -   Fluorescein defects are significantly correlated with visual        field loss and retinal nerve fiber layer loss. The second        circulatory defect is a decrease of flow of fluorescein in the        retinal vessels, especially the retinal veins, so that the        greater the age, diastolic blood pressure, ocular pressure and        visual field loss , the less the flow. Both the optic disk and        retinal circulation defects occur in untreated ocular        hypertensive eyes. These observations indicate that circulatory        defects in the optic disk and retina occur in ocular        hypertension and open-angle glaucoma and increase with the        progression of the disease.

Thus, it is evident that there is an unmet need for agents that haveneuroprotective effects in the eye that can stop or retard theprogressive damage that occurs to the nerves as a result of glaucoma orother ocular afflictions.

Prostaglandins were earlier regarded as potent ocular hypertensives;however, evidence accumulated in the last two decades shows that someprostaglandins are highly effective ocular hypotensive agents and areideally suited for the long-term medical management of glaucoma. (See,for example, Starr, M. S. Exp. Eve Res. 1971, 11, pp. 170-177; Bito, L.Z. Biological Protection with Prostaglandins Cohen, M. M., ed., BocaRaton, Fla., CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., AppliedPharmacology in the Medical Treatment of Glaucomas Drance, S. M. andNeufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505).Such prostaglandins include PGF_(2α′) PGF_(1α′) PGE₂, and certainlipid-soluble esters, such as C₁ to C₅ alkyl esters, e.g. 1-isopropylester, of such compounds.

BRIEF SUMMARY OF THE INVENTION

The present invention provides novel compounds, having the formula

wherein the dotted line indicates the presence or absence of a bond;

-   R is selected from the group consisting of halo, C₁-C₁₀ alkyl,    C₁-C₁₀ alkoxy, hydroxy and NR⁴R⁵;-   R¹ is selected from the group consisting of C₁-C₁₀ alkoxy, OH and    NR⁴R⁵;-   R² is selected from the group consisting of C₁-C₁₀ alkyl ,    heteroaryl, carbocyclic aryl, e.g. phenyl, and (CH₂)_(n)OH;-   R³ is selected from the group consisting of C₁-C₁₀ alkyl,    heteroaryl, carbocyclic aryl, e,g. phenyl, mono, -di-,    tri-substituted carbocyclic aryl, e.g. phenyl and heteroaryl;-   R⁴ and R⁵ are independently selected from the group consisting of H,    C₁-C₁₀ alkyl, C₁-C₁₀ alkyl hydroxyl;    X is OH or CO;-   c is 0 or 1;-   d is 0 or 1, and when c is 0, d is 1 and when d is 0, c is 1;-   e is 0 or 1, and when d is 1, e is 0;-   f is 0 or 1;-   g is 1 or 2;-   x is 0 or 1;-   y is 0 or 1, and when y is 1, x is 1;-   a is 0 or 1 or 2;    b is 0 or 1, provided however when X is CO, a is 0;-   z is 0, 1,2 or 3; and-   n is 0 or1.

The present compounds are useful in lowering intraocular pressure and/orglaucoma. These compounds also provide neuroprotection to the eye of ahuman.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 describes a general synthetic scheme to show the preparation ofan intermediate which for the preparation of the compounds of thisinvention.

FIG. 2 describes a general synthetic scheme to show the preparation ofthe compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention have the general formula I

wherein the dotted line indicates the presence or absence of a bond;

-   R is selected from the group consisting of halo, C₁-C₁₀ alkyl,    C₁-C₁₀ alkoxy, hydroxy and NR⁴R⁵;-   R¹ is selected from the group consisting of C₁-C₁₀ alkoxy, OH and    NR⁴R⁵;-   R² is selected from the group consisting of C₁-C₁₀ alkyl ,    heteroaryl, carbocyclic aryl, e.g. phenyl, and (CH₂)_(n)OH;-   R³ is selected from the group consisting of C₁-C₁₀ alkyl,    heteroaryl, carbocyclic aryl, e,g. phenyl, mono, -di-,    tri-substituted carbocyclic aryl, e.g. phenyl and heteroaryl;-   R⁴ and R⁵ are independently selected from the group consisting of H,    C₁-C₁₀ alkyl, C₁-C₁₀ alkyl hydroxyl;    X is OH or CO;-   c is 0 or 1;-   d is 0 or 1, and when c is 0, d is 1 and when d is 0, c is 1;-   e is 0 or 1, and when d is 1, e is 0;-   f is 0 or 1;-   g is 1 or 2;-   x is 0 or 1;-   y is 0 or 1, and when y is 1, x is 1;-   a is 0 or 1 or2;    b is 0 or 1, provided however when X is CO, a is 0;-   z is 0, 1, 2 or 3; and-   n is 0 or 1.    Heteroaryl includes mono and bicyclic compounds having from 3 to 10    carbon atoms and from 1 to 4 heteroatoms, e.g. N, S, and/or O atoms,    in the ring(s). Carbocyclic aryl includes mono and bicyclic    compounds having from 6 to 10 carbon atoms in the ring.    In one aspect of this invention, the compounds are represented by    general formula II:    In another aspect of the invention, in the novel compounds of    formula I, y is 1, z is 2 and R is chloro or y is 0, x is 0, z is 0,    n is 0 and R³ is t-butyl.    Preferably R¹ is OH or O-lower alkyl or N(H)_(n)(lower alkyl)_(m) or    N(H)_(n) (lower alkyl hydroxyl)_(m) wherein n is 0 or 1 and m is 1    or 2. Lower alkyl is defined as a C₁ to C₆ alkyl.    More preferably R¹ is OH or OCH₃.    Preferably the n associated with R² is 1 and R² is lower alkyl.    R³ is preferably selected from the group consisting of phenyl,    furanyl and thienyl.    Finally, preferably the benzylic OH group is oriented as an α OH    group.    Specific compounds of the invention include:-   7-[[4-(1-Hydroxyhexyl)benzyl]methanesulfonylamino]heptanoic acid    ethyl ester (11).-   7-[[4-(1-Hydroxyhexyl)benzyl]methanesulfonylamino]heptanoic acid    (12).-   7-[[4-(1-hydroxyhexyl)benzyl]methanesulfonylamino]hept-5-yne-oic    acid-   7-[[4-(2,6-dichlorophenyloxyethyl]methanesulfonylamino]hept-5-yne-oic    acid-   7-[[4-(2,6-dichlorophenyloxyethyl]methanesulfonylamino]hept-5-ene-oic    acid-   7-[[4-(1-t-butyl)benzyl]methanesulfonylamino]heptanoic acid-   7-[[4-(1-t-butyl)benzyl]benzenesulfonylamino]heptanoic acid-   7-[[4-(1-t-butyl)benzyl]pyridinesulfonylamino]heptanoic acid-   7-[[4-(1-t-butyl)benzyl]thiophenelsulfonylamino]heptanoic acid-   7-[[4-(1-hydroxyhexyl)benzyl]thiophenesulfonylamino]heptanoic acid-   7-[[4-(1-hydroxyhexyl)benzyl]benzenesulfonylamino]heptanoic acid-   7-[[4-(1-hydroxyhexyl)benzyl]pyridinesulfonylamino]heptanoic acid-   4-[[4-(1-hydroxyhexyl)benzyl]pyridinesulfonylaminomethyl]    phenoxyacetic acid-   4-[[4-(1-t-butyl)benzyl]pyridinesulfonylaminomethyl] phenoxyacetic    acid

The compounds of the invention are especially useful in treating ocularhypertension, i.e. lowering elevated intraocular pressure (IOP), and/orglaucoma. These compounds are useful in providing neuroprotection to theeye of a human.

Pharmaceutical compositions including the compounds of this inventionmay be prepared by combining a therapeutically effective amount of atleast one compound according to the present invention, or apharmaceutically acceptable salt thereof, as an active ingredient, withconventional ophthalmically acceptable pharmaceutical excipients, and bypreparation of unit dosage forms suitable for topical ocular use. Thetherapeutically efficient amount typically is between about 0.0001 andabout 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquidformulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 4.5 and 8.0with an appropriate buffer system, a neutral pH being preferred but notessential. The formulations may also contain conventional,pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose cyclodextrin and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace of or in conjunction with it.

The ingredients are usually used in the following amounts: IngredientAmount (% w/v) active ingredient about 0.001-5 preservative   0-0.10vehicle  0-40 tonicity adjustor  0-10 buffer 0.01-10   pH adjustor q.s.pH 4.5-8.0 antioxidant as needed surfactant as needed purified water asneeded to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations for use in the method of the presentinvention are conveniently packaged in forms suitable for meteredapplication, such as in containers equipped with a dropper, tofacilitate application to the eye. Containers suitable for dropwiseapplication are usually made of suitable inert, non-toxic plasticmaterial, and generally contain between about 0.5 and about 15 mlsolution. One package may contain one or more unit doses.

Especially preservative-free solutions are often formulated innon-resealable containers containing up to about ten, preferably up toabout five units doses, where a typical unit dose is from one to about 8drops, preferably one to about 3 drops. The volume of one drop usuallyis about 20-35 μl.

The invention is further illustrated by the following examples which areillustrative of a specific mode of practicing the invention and are notintended as limiting the scope of the claims. (The numbers of thecompounds in the Examples correspond to the numbers in the Figures.)

EXAMPLE 1

7-Azidoheptanoic Acid Ethyl Ester (2).

Sodium azide (1.7 g, 0.026 mol) was added to ethyl 7-bromoheptanoate 1(4,1 g, 0.017 mol) in DMF (40 mL) at 23° C. The reaction was stirred for16 h, diluted with pentane and washed with water. The organic portionwas washed with brine, dried (MgSO₄), filtered and concentrated in vacuoto give 3.22 g (95%) of the azide 2 as a clear, colorless liquid.

EXAMPLE 2

7-Aminoheptanoic Acid Ethyl Ester (3).

Triphenyphosphine (4.6 g, 17.5 mmol) was added to a solution of theazide (17.0 mmol) in THF (68 mL) at 23° C. After stirring for 16 h H₂O(0.46 mL, 25.5 mmol) was added. The reaction was stirred another 16 hand the solvent was removed in vacuo. The residue was diluted withhexane and the white precipitate was removed by vacuum filtration. Thefiltrate was concentrated in vacuo to afford the crude amine 3 as ayellow oil.

EXAMPLE 3

7-Methanesulfonylaminoheptanoic Acid Ethyl Ester (4).

Methanesulfonyl chloride (1.6 mL, 20.0 mmol) was added to a solution ofthe amine (afforded in the above step) and pyridine (2.1 mL, 25.5 mmol)in CH₂Cl₂ (34 mL) at 0° C. The reaction was allowed to warm to roomtemperature and stirred for an additional 12 h. The reaction solutionwas diluted with Et₂O and washed with 1 N HCl, saturated aqueous NaHCO₃and brine. The organic portion was dried (MgSO₄), filtered andconcentrated in vacuo. Flash column chromatography (FCC) (silica gel,1:1 hex/EtOAc) gave 2.4 g (60%) of the sulfonamide 4 as a white powder.

EXAMPLE 4

1-(4-Bromophenyl)hexan-1-ol (6).

n-Pentylmagnesium bromide (12.1 mL of a 2.0 M solution in Et₂O, 24.0mmol) was added to a solution of 4-bromobenzaldehyde 5 (4.0 g, 22.0mmol) at −78° C. The reaction was then warmed to room temperature for0.5 h and quenched with saturated aqueous NH₄Cl. The mixture wasextracted with EtOAc and the organic portion was washed with brine,dried (MgSO₄), filtered and concentrated in vacuo. FCC (silica gel, 9:1hex/EtOAc) gave 3.6 g (63%) of the alcohol 6 as a clear, colorless oil.

EXAMPLE 5

[1-(4-Bromophenyl)hexyloxy]-tert-butyidimethyl Silane (7).

t-Butyidimethylsilylchloride (2.49 g, 16.5 mmol) was added to a solutionof the alcohol 6 3.6 g, 14.0 mmol) and imidazole (1.91 g, 28.0 mmol) inDMF (22 mL) at 23° C. The reaction was stirred for 16 h, diluted withEt₂O and washed with 1 N HCl, saturated aqueous NaHCO₃ and brine. Theorganic portion was dried (MgSO₄), filtered and concentrated in vacuo.FCC (silica gel, 100% hex) afforded 5.18 g (63%) of the silyl ether 7 asa clear, colorless oil.

EXAMPLE 6

[4-[1-(tert-butyldimethylsilanyloxy)hexyl]phenyl]methanol (8).

tert-Butyllithium (6.6 mL of a 1.7 M solution in pentane, 11.32 mmol)was added to a solution of the aryl bromide 7 (2.0 g, 5.39 mmol) in THF(22 mL) at −78° C. After 0.5 h paraformaldehyde (323 mg, 8.09 mmol) wasadded. The reaction was warmed to room temperature and stirred for 16 h.The reaction was quenched with saturated aqueous NH₄Cl and extractedwith EtOAc. The organic portion was dried (MgSO₄), filtered andconcentrated in vacuo. FCC (silica gel, 6:1 hex/EtOAc) yielded 1.2 g(69%) of the alcohol 8 as a clear, colorless oil.

EXAMPLE 7

tert-Butyl[1-(4-iodomethylphenyl)hexyloxy]dimethylsilane (9).

Iodine (503 mg, 1.98 mmol) was added to a solution of triphenylphosphine(520 mg, 1.98 mmol) and imidazole (169 mg, 2.48 mmol) in CH₂Cl₂ (7.0 mL)at 23° C. After 0.5 h a solution of the alcohol (532 mg, 1.65 mmol) inCH₂Cl₂ (3.0 mL) was added. The reaction was stirred for 1 h, dilutedwith hexane and then filtered through celite. The filtrate wasconcentrated in vacuo and purified by FCC (silica gel, 100% hex) to give700 mg (98%) of the iodide 9 as a clear, colorless oil.

EXAMPLE 8

7-[[4-(1-(tert-Butyldimethylsilanyloxy)hexyl)benzyl]methanesulfonylamino]-heptanoicAcid Ethyl Ester (10).

Sodium bis(trimethylsilyl)amide (1.0 mL of a 1.0 M solution in THF, 1.00mmol) was added to a solution of the sulfonamide 4 (220 mg, 0.88 mmol)in THF (2.2 mL) at 0° C. The reaction was warmed to room temperature anda solution of the iodide 9 (432 mg, 1.00 mmol) in THF (3.0 mL) wasadded. The reaction was stirred at room temperature for 16 h, quenchedwith saturated aqueous NH₄Cl and extracted with EtOAc. The organicportion was washed with brine, dried (MgSO₄), filtered and concentratedin vacuo. FCC (silica gel, 4:1 hex/EtOAc) gave 159 mg (29%) of the silylether 10 as a light yellow viscous oil.

EXAMPLE 9

7-[[4-(1-Hydroxyhexyl)benzyl]methanesulfonylamino]heptanoic Acid EthylEster (11).

Tetrabutylammonium fluoride (0.6 mL of a 1.0 M solution in THF, 0.6mmol) was added to a solution of the silylether 10 (159 mg, 0.29 mmol)in THF (3.0 mL) at 23° C. The reaction was stirred for 16 h, dilutedwith EtOAc and washed with water. The organic portion was washed withbrine, dried (MgSO₄), filtered and concentrated in vacuo. FCC (silicagel, 2:1 hex/EtOAc) afforded 118.6 mg (94%) of the alcohol 11 as a lightyellow, viscous oil.

EXAMPLE 10

7-[[4-(1-Hydroxyhexyl)benzyl]methanesulfonylamino]heptanoic Acid (12).

Lithium hydroxide (0.47 mL of a 0.5 N solution in H₂O, 0.236 mmol) wasadded to a solution of the ester 11 (52 mg, 0.118 mmol) in THF (1.5 mL)at 23° C. The reaction mixture was stirred for 16 h, acidified with 1 NHCl and extracted with EtOAc. The organic portion was washed with brine(2×), dried (MgSO₄), filtered and concentrated in vacuo. FCC (silicagel, 100% EtOAc) gave 36.2 mg (72%) of the free acid 12 as a lightyellow, viscous oil.

In an in-vitro assay for binding to and activity at variousprostaglandin receptors, the compound of Example 10 was shown to beselective at the EP2 and EP4 receptors as compared to the FP, EP1, TP,IP and DP receptors.

The corresponding derivatives of the compound of Example 10, wherein themethane sulfonyl group is replaced by a thiophene sulfonyl, benzenesulfonyl or a pyridine sulfonyl group are also EP2 and EP4 ligands. SeeTable 1 below. TABLE 1 Compound cAMP bhEP₂ fhEP₂ bhEP₄ fhEP₄

16 1695 406 15K 15K

>10K 1490 600 90 50K

634 150 50K

138 4732 275 546 50K

Other compounds of the invention wherein the δ phenyl group of thecompound of Example 10 is substituted with a t-butyl or two chlorogroups or an oxa radical is incorporated into the δ chain or a phenyloxaradical is incorporated in the α chain or the α chain is unsaturated areEP2 ligands as shown in Table 2 below.

These compounds are prepared by substituting the appropriate reactantfor reactant 1 of FIG. 1 or reactant 9 of FIGS. 1 and 2 for thedesignated reactants 1 and 9 of the Examples. TABLE 2 Sig- cAMP Ca²⁺signal EP₂ Binding Ca²⁺ nal EP₄ Binding EC₅₀ % EC₅₀ % EC₅₀ % EC₅₀ % EC₅₀Compound (nM) PGE₂ (nM) Inh (nM) PGE₂ (nM) Inh (nM)

 24  620 5675 NA NA NA NA NA 2921

214 83 2958 81 1900 10  NA 64 2921 IP = 403 TP = 7008

 84 90 1249 87 1126 5 NA 55 4166 IP = 868

156 89 2313 60 NA 2 NA 41 NA IP = 2561

965 78  964 82 1540 11  NA 99  373

126 83  591 73  829 1 NA 71 1376

1968  71 1132 76  493 9 NA 94 706

   3.5 92  11 97  208 2 NA 89 1321 EP3 = 1150 DP = 99

 18   (5) 87  20 93  100  (50) 0 NA 59 1345 (>3200)  

While particular embodiments of the invention have been described itwill be understood of course that the invention is not limited theretosince many obvious modifications can be made and it is intended toinclude within this invention any such modifications as will fall withinthe scope of the appended claims.

1. A novel compound having the formula:

wherein the dotted line indicates the presence or absence of a bond; Ris selected from the group consisting of halo, C₁-C₁₀ alkyl, C₁-C₁₀alkoxy, hydroxy and NR⁴R⁵; R¹ is selected from the group consisting ofC₁-C₁₀ alkoxy, OH and NR⁴R⁵; R² is selected from the group consisting ofC₁-C₁₀ alkyl , heteroaryl, phenyl and (CH₂)_(n)OH; R³ is selected fromthe group consisting of C₁-C₁₀ alkyl, heteroaryl, phenyl, mono, -di-,tri-substituted phenyl and heteroaryl; R⁴ and R⁵ are independentlyselected from the group consisting of H, C₁-C₁₀ alkyl, C₁-C₁₀ alkylhydroxyl; X is OH or CO; c is 0 or 1; d is 0 or 1, and when c is 0, d is1 and when d is0 c is 1; e is 0 or 1, and when d is 1, e is 0; f is 0 or1; g is 1 or 2; x is 0 or 1; y is 0 or 1, and when y is 1, x is 1; a is0 or 1 or2; b is 0 or 1, provided however when X is CO, a is 0; z is 0,1, 2 or 3; and n is 0 or
 1. 2. The compound of claim 1 wherein R ³ isselected from the group consisting of thienyl, furanyl and pyridyl. 3.The compound of claim 1 wherein R³ is selected from the group consistingof C₁-C₁₀ alkyl.
 4. The compound of claim 1 wherein R¹ is OH or O-loweralkyl, wherein said lower alkyl is a C₁-C₆ alkyl.
 5. The compound ofclaim 1 wherein R¹ is selected from the group consisting ofN(H)_(n)(lower alkyl)_(m) or N(H)_(n) (lower alkylhydroxyl)m whereinsaid lower alkyl is a C₁-C₆ alkyl and wherein n is 0 or 1 and m is 1 or2.
 6. The compound of claim 1 wherein R² is a C₁-C₆ lower alkyl and then associated with R² is
 1. 7. The compound of claim 1 wherein X is OH.8. The compound of claim 1 wherein R is selected from the groupconsisting of chloro and t-butyl.
 9. The compound of claim 1 wherein dis 1 and f is
 1. 10. The compound of claim 1 wherein y is
 1. 11. Thecompound of claim 1 selected from the group consisting of7-[[4-(1-Hydroxyhexyl)benzyl]methanesulfonylamino]heptanoic acid ethylester, 7-[[4-(1-Hydroxyhexyl)benzyl]methanesulfonylamino]heptanoic acid,7-[[4-(1-hydroxyhexyl)benzyl]methanesulfonylamino]hept-5-yne-oic acid7-[[4-(2,6-dichlorophenyloxyethyl]methanesufonylamino]hept-5-yne-oicacid7-[[4-(2,6-dichlorophenyloxyethyl]methanesulfonylamino]hept-5-ene-oicacid 7-[[4-(1-t-butyl)benzyl]methanesulfonylamino]heptanoic acid7-[[4-(1-t-butyl)benzyl]benzenesulfonylamino]heptanoic acid7-[[4-(1-t-butyl)benzyl]pyridinesulfonylamino]heptanoic acid7-[[4-(1-t-butyl)benzyl]thiophenelsulfonylamino]heptanoic acid7-[[4-(1-hydroxyhexyl)benzyl]thiophenesulfonylamino]heptahoic acid7-[[4-(1-hydroxyhexyl)benzyl]benzenesulfonylamino]heptanoic acid7-[[4-(1-hydroxyhexyl)benzyl]pyridinesulfonylamino]heptanoic acid4-[[4-(1-hydroxyhexyl)benzyl]pyridinesulfonylaminomethyl] phenoxyaceticacid and 4-[[4-(1-t-butyl)benzyl]pyridinesulfonylaminomethyl]phenoxyacetic acid.
 12. A method for treating ocular hypertension orglaucoma which comprises administering to a mammal having ocularhypertension a therapeutically effective amount of a compound of theformula

wherein the dotted line indicates the presence or absence of a bond; Ris selected from the group consisting of halo, C₁-C₁₀ alkyl, C₁-C₁₀alkoxy, hydroxy and NR⁴R⁵; R¹ is selected from the group consisting ofC₁-C₁₀ alkoxy, OH and NR⁴R⁵; R² is selected from the group consisting ofC₁-C₁₀ alkyl , heteroaryl, phenyl and (CH₂)_(n)OH; R³ is selected fromthe group consisting of C₁-C₁₀ alkyl, heteroaryl, phenyl, mono, -di-,tri-substituted phenyl and heteroaryl; R⁴ and R⁵ are independentlyselected from the group consisting of H, C₁-C₁₀ alkyl, C₁-C₁₀ alkylhydroxyl; X is OH or CO; c is 0 or 1; d is 0 or1, and when c is 0, d is1 and when d is 0,c is 1; e is 0 or 1, and when d is 1 e is 0; f is 0 or1; g is 1 or 2; x is 0 or 1; y is 0 or 1, and when y is 1,x is 1; a is 0or 1 or2; b is 0 or 1, provided however when X is CO, a is 0; z is 0, 1,2or 3; and n is 0 or
 1. 13. The method of claim 1 wherein R³ is selectedfrom the group consisting of thienyl, furanyl and pyridyl.
 14. Themethod of claim 1 wherein R³ is selected from the group consisting ofC₁-C₁₀ alkyl.
 15. The method of claim 1 wherein R¹ is OH or O-loweralkyl, wherein said lower alkyl is a C₁-C₆ alkyl.
 16. The method ofclaim 1 wherein R¹ is selected from the group consisting ofN(H)_(n)(lower alkyl)_(m) or N(H)_(n) (lower alkylhydroxyl)m whereinsaid lower alkyl is a C₁-C₆ alkyl and wherein n is 0 or 1 and m is 1 or2.
 17. The method of claim 1 wherein R² is a C₁-C₆ lower alkyl and the nassociated with R² is
 1. 18. The compound of claim 1 wherein X is OH.19. The compound of claim 1 wherein R is selected from the groupconsisting of chloro and t-butyl.
 20. The compound of claim 1 wherein dis 1 and f is
 1. 21. The compound of claim 1 wherein y is
 1. 22. Themethod of claim 12 selected from the group consisting of7-[[4-(1-Hydroxyhexyl)benzyl]methanesulfonylamino]heptanoic acid ethylester, 7-[[4-(1-Hydroxyhexyl)benzyl]methanesulfonylamino]heptanoic acid7-[[4-(1-hydroxyhexyl)benzyl]methanesulfonylamino]hept-5-yne-oic acid7-[[4-(2,6-dichlorophenyloxyethyl]methanesulfonylamino]hept-5-yne-oicacid7-[[4-(2,6-dichlorophenyloxyethyl]methanesulfonylamino]hept-5-ene-oicacid 7-[[4-(1-t-butyl)benzyl]methanesulfonylamino]heptanoic acid7-[[4-(1-t-butyl)benzyl]benzenesulfonylamino]heptanoic acid7-[[4-(1-t-butyl)benzyl]pyridinesulfonylamino]heptanoic acid7-[[4-(1-t-butyl)benzyl]thiophenelsulfonylamino]heptanoic acid7-[[4-(1-hydroxyhexyl)benzyl]thiophenesulfonylamino]heptanoic acid7-[[4-(1-hydroxyhexyl)benzyl]benzenesulfonylamino]heptanoic acid7-[[4-(1-hydroxyhexyl)benzyl]pyridinesulfonylamino]heptanoic acid4-[[4-(1-hydroxyhexyl)benzyl]pyridinesulfonylaminomethyl] phenoxyaceticacid and 4-[[4-(1-t-butyl)benzyl]pyridinesulfonylaminomethyl]phenoxyacetic acid.
 23. An ophthalmic solution comprising atherapeutically-effective amount of the compound of claim 1 inophthalmically-acceptable vehicle.
 24. The solution of claim 23 whereinsaid vehicle is saline.
 25. The solution of claim 23 wherein saidcompound comprises from 0.001-5% w/v of said solution.
 26. A method ofproviding neuroprotection to the eye of a mammal which comprisesadministering to the eye of said mammal a novel compound having theformula:

wherein the dotted line indicates the presence or absence of a bond; Ris selected from the group consisting of halo, C₁-C₁₀ alkyl, C1-C1oalkoxy, hydroxy and NR⁴R⁵; R¹ is selected from the group consisting ofC₁-C₁₀ alkoxy, OH and NR⁴R⁵; R² is selected from the group consisting ofC₁-C₁₀ alkyl , heteroaryl, phenyl and (CH₂)_(n)OH; R³ is selected fromthe group consisting of C₁-C₁₀ alkyl, heteroaryl, phenyl, mono, -di-,tri-substituted phenyl and heteroaryl; R⁴ and R⁵ are independentlyselected from the group consisting of H, C₁-C₁₀ alkyl, C₁-C₁₀ alkylhydroxyl; X is OH or CO; c is 0 or 1; d is 0 or 1, and when c is 0, d is1 and when d is 0, c is 1; e is 0 or 1, and when d is 1, e is 0; f is 0or 1; g is 1 or 2; x is 0 or 1; y is 0 or1, and when y is 1,x is 1; a is0 or 1 or2; b is 0 or 1, provided however when X is O, a is 0; z is 0,1, 2 or3; and n is 0 or
 1. 27. The compound of claim 1 wherein R³ isselected from the group consisting of thienyl, furanyl and pyridyl. 28.The compound of claim 1 wherein R³ is selected from the group consistingof C₁-C₁₀ alkyl.
 29. The compound of claim 1 wherein R¹ is OH or O-loweralkyl, wherein said lower alkyl is a C₁-C₆ alkyl.
 30. The compound ofclaim 1 wherein R¹ is selected from the group consisting ofN(H)_(n)(lower alkyl)_(m) or N(H)_(n) (lower alkylhydroxyl)m whereinsaid lower alkyl is a C₁-Cr₆ alkyl and wherein n is 0 or 1 and m is 1 or2.
 31. The compound of claim 1 wherein R² is a C₁-C₆ lower alkyl and then associated with R² is
 1. 32. The compound of claim 1 wherein X is OH.33. The compound of claim 1 wherein R is selected from the groupconsisting of chloro and 7-butyl.
 34. The compound of claim 1 wherein dis 1 and f is
 1. 35. The compound of claim 1 wherein y is
 1. 36. Thecompound of claim 1 selected from the group consisting of7-[[4-(1-Hydroxyhexyl)benzyl]methanesulfonylamino]heptanoic acid ethylester 7-[[4-(1-hydroxyhexyl)benzyl]methanesulfonylamino]hept-5-yne-oicacid7-[[4-(2,6-dichlorophenyloxyethyl]methanesulfonylamino]hept-5-yne-oicacid7-[[4-(2,6-dichlorophenyloxyethyl]methanesulfonylamino]hept-5-ene-oicacid 7-[[4-(1-t-butyl)benzyl]methanesulfonylamino]heptanoic acid7-[[4-(1-t-butyl)benzyl]benzenesulfonylamino]heptanoic acid7-[[4-(1-t-butyl)benzyl]pyridinesulfonylamino]heptanoic acid7-[[4-(1-t-butyl)benzyl]thiophenelsulfonylamino]heptanoic acid7-[[4-(1-hydroxyhexyl)benzyl]thiophenesulfonylamino]heptanoic acid7-[[4-(1-hydroxyhexyl)benzyl]benzenesulfonylamino]heptanoic acid7-[[4-(1-hydroxyhexyl)benzyl]pyridinesulfonylamino]heptanoic acid4-[[4-(1-hydroxyhexyl)benzyl]pyridinesulfonylaminomethyl] phenoxyaceticacid and 4-[[4-(1-t-butyl)benzyl]pyridinesulfonylaminomethyl]phenoxyacetic acid.